Is EGFR p.Ser4Tyr (c.11C>A) pathogenic?

EGFR p.Ser4Tyr (c.11C>A) is classified Conflicting classifications of pathogenicity in EGFR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-18). AlphaMissense: likely benign (0.1277); Very rare (popmax 0.00197%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with EGFR p.Ser4Tyr (c.11C>A)?

EGFR p.Ser4Tyr (c.11C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is EGFR p.Ser4Tyr (c.11C>A) in the general population?

EGFR p.Ser4Tyr (c.11C>A) is very rare (popmax 0.00197%, amr) (gnomAD).

What do computational predictors say about EGFR p.Ser4Tyr (c.11C>A)?

AlphaMissense predicts likely benign (score 0.1277) — an in-silico prediction, not a clinical call.

EGFR p.Ser4Tyr

c.11C>A · rs771210838 · VCV957645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1277 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00197%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1277	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -9.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.01	GERP -2.5
Regional constraint	o/e 1.72	unconstrained · MANE · 84 bp · p 9.2e-06 · regional, not allelic
Overall
CADD	14.23	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00197% Admixed American · 1/50,822 alleles

Overall 0.000148% 2/1,354,588 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00197%	50,822
European (non-Finnish)	8.91e-05%	1,122,224

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EGFR
Protein: p.Ser4Tyr
Coding: c.11C>A
MANE Select: NM_005228
dbSNP: rs771210838
Type: single nucleotide variant
Location: chr7:55019288 (GRCh38)
Gene constraint: LOEUF 0.475 · pLI 0.98 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.29 · 393 PDB

Full EGFR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EGFR p.Ser4= Likely benign ★★ same residue
EGFR p.Ser4Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
EGFR p.Ser4Cys Uncertain significance ★ ⚠ same residue
EGFR c.1207+5G>A Uncertain significance ★★ same condition
EGFR c.1298+3A>G Uncertain significance ★★ same condition
EGFR c.1298+4A>G Uncertain significance ★★ same condition
EGFR c.1298+6T>C Uncertain significance ★★ same condition
EGFR c.1499-3C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/egfr-p-ser4tyr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown